This application addresses broad Challenge area (15) Translational Science and specific Challenge Topic, 15-CA-101: The Role of Cellular Architecture in Normal and Tumor Cell Biology. New blood vessels are formed throughout life by either vasculogenic or angiogenic processes. During neovessel development, endothelial cell responses to pro-angiogenic signals are governed by the structural and biophysical remodeling of the surrounding 3-dimensional extracellular matrix. However, the mechanisms by which matrix-derived cues are integrated with the growth factor-initiated genetic programs that underlie morphogenesis remain largely undefined. In preliminary studies, we have succeeded in identifying a novel regulatory axis wherein extracellular matrix remodeling regulates neovessel development by controlling nuclear architecture, chromatin organization, and transcriptional competence of the genome under 3- dimensional-specific conditions. Transduction of extracellular matrix -derived signals to the nucleus requires functional interactions between the cytoskeleton, actomyosin, generated mechanical tension and Klarsicht, ANC-1, Syne homology domain-containing cytoplasmic proteins which transmit signals to the lamin-rich nuclear scaffold via members of the SUN protein family. These findings outline a novel endothelial cell mechanotransduction program that governs vasculogenesis/angiogenesis by transmitting biophysical signals received from the dynamically remodeled 3-D extracellular matrix to the nuclear compartment. As such, we propose to;i) characterize nuclear organization dynamics during 3-D neovessel formation, ii) define the role of extracellular matrix remodeling as an upstream regulator of nuclear architecture and transcriptional machinery and iii) characterize the cytoskeletal/nesprin/SUN/lamin axis as the transduction pathway of extracellular matrix-derived cues to the nuclear compartment. Taken together, these studies are designed to characterize a novel mechanotransduction program wherein endothelial cells purposely reshape nuclear architecture and function to regulate vasculogenesis and angiogenesis. Further, as normal cell types - ranging from stem cells to chondrocytes and adipocytes - as well as neoplastic cell populations similarly reside within a dynamically remodeling extracellular matrix, we posit that the mechanistic processes outlined in this proposal will have broad implications for controlling cell functions in health and disease. Public Health Relevance: These studies are designed to characterize a novel mechanotransduction program wherein endothelial cells purposely reshape nuclear architecture and function to regulate vasculogenesis by relaying biophysical signals received from the dynamically remodeled 3-dimensional extracellular matrix to the nucleus.